US10414788B2 - Substituted thienopyrrolopyrimidine ribonucleosides for therapeutic use - Google Patents

Substituted thienopyrrolopyrimidine ribonucleosides for therapeutic use Download PDF

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Publication number
US10414788B2
US10414788B2 US16/098,068 US201616098068A US10414788B2 US 10414788 B2 US10414788 B2 US 10414788B2 US 201616098068 A US201616098068 A US 201616098068A US 10414788 B2 US10414788 B2 US 10414788B2
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amino
pyrimidine
thieno
pyrrolo
ribofuranosyl
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US20190144487A1 (en
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Michal Hocek
Michal TICHY
Marian Hajduch
Petr Dzubak
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Institute of Organic Chemistry and Biochemistry CAS
Univerzita Palackeho V Olomouci
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Institute of Organic Chemistry and Biochemistry CAS
Univerzita Palackeho V Olomouci
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention provides new type of compounds with anti-cancer activity and their therapeutic use.
  • Pyrimidoindole ribonucleosides and 8H-thieno[2′,3′:4,5]pyrrolo[2,3-d]pyrimidine ribonucleosides prepared in our group are the only known types of annulated deazapurine nucleosides, however, they displayed only minor or no cytotoxicity (formula C, ref.: Tich ⁇ , M. et al., Bioorg. Med. Chem. 2012, 20, 6123-6133; Tich ⁇ , M. et al., Bioorg. Med. Chem. 2013, 21, 5362-5372).
  • This invention describes new 4-substituted 8H-thieno[3′,2′:4,5]pyrrolo[2,3-d]pyrimidine ribonucleosides exhibiting strong cytostatic and cytotoxic effects on cell lines preferentially of tumor origin and on broad spectrum of cancers of various histogenetic origin.
  • the specific fused-ring skeleton comprising heteroatoms in the specified locations makes these compounds significantly different from all previously prepared 7-deazapurine derivatives of general formulas A and B as well as from pyrimidoindole ribonucleosides of general formula C.
  • Thienopyrrolopyrimidine bases themselves are a new class of compounds, which was not described previously. These compounds are unknown in nature. Hence, their biological activity has not yet been studied.
  • Thienopyrrolopyrimidine nucleosides are a new and unique type of nucleosides with a rigid tricyclic base, which leads to a new type of interaction with biological systems and therefore to a different mechanism of action than all the other 7-substituted 7-deazapurine nucleosides exhibit.
  • This invention provides substituted thienopyrrolopyrimidine ribonucleosides of general formula I:
  • R is selected from the group comprising
  • R is selected from the group comprising C1-C5 alkyl, phenyl, naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, dibenzofuryl, amino, C1-C5 alkylamino, di(C1-C5 alkyl) amino, C1-C5 alkoxy, C1-C5 alkylsulfanyl.
  • R is selected from the group comprising furan-2-yl, furan-3-yl, benzofuran-2-yl, methylsulfanyl, methoxy, amino, dimethylamino or methyl.
  • Formula I includes all possible optical isomers of the compounds, and mixtures of optical isomers, including racemic mixtures.
  • the term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto (e.g., phenol or hydroxyamic acid).
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable.
  • Lists of additional suitable salts can be found, e.g., in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), which is herein incorporated by reference.
  • the present invention provides the following thienopyrrolopyrimidine ribonucleosides of formula I:
  • the present invention provides a compound of formula I for use as a medicament.
  • the present invention provides substituted thienopyrrolopyrimidine ribonucleosides of formula I for use in inhibition of pathological cell proliferation of tumor/non-tumor origin and/or in a method of treatment of tumor/non-tumor disease associated with cell hyperproliferation.
  • the present invention provides substituted thienopyrrolopyrimidine ribonucleosides of formula I for the preparation of a medicament for treatment of tumor/cancer diseases, covering e.g. epithelial, mesenchymal and neuroectoderm origin tumors.
  • the present invention provides a method of treatment of tumor/cancer diseases, such as epithelial, mesenchymal and neuroectodermal origin tumors, comprising the step of administering at least one compound of formula I to a patient in need of such treatment.
  • tumor/cancer diseases such as epithelial, mesenchymal and neuroectodermal origin tumors
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I and one or more pharmaceutically acceptable carriers, fillers and/or excipients.
  • the invention also provides the above mentioned pharmaceutical composition for use in the inhibition of pathological cell proliferation of tumor/non-tumor origin and/or in the treatment of tumor/non-tumor disease associated with cell hyperproliferation.
  • therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will be effective in treating a disease or disorder in a human or mammalian.
  • therapeutically effective amount of drug can reduce the amount of cancer cells, the tumor size; inhibit (slow down to certain extent or preferably stop) cancer cell infiltration into peripheral organs; inhibit, i.e. slow down or stop tumor metastasis; inhibit at least to some extent tumor growth and/or relieve at least to some extent one or more symptoms associated with tumor or cancer.
  • composition refers to a formulation of a compound and a medium generally accepted in the art for the delivery of biologically active agents to a mammal, e.g. to a human
  • a medium includes pharmaceutically acceptable carriers, diluents or adjuvants.
  • the term “pharmaceutically acceptable carrier, filler or excipient” includes excipients, carriers, lubricants, sweetening agents, preservatives, dyes, flavoring agents, surfactants, disintegration agents, suspending agents, drug stabilizers, isotonic agents, solvents, or emulsifiers which have been approved for use in humans or domestic animals.
  • the invention further provides compounds of formula I for use in the form of an active substance of a pharmacologically acceptable composition, which can be made by common procedures known in the field, e.g. the active substance can be bound to or mixed with pharmaceutically acceptable inert organic and/or inorganic carriers/excipients.
  • the invention also provides compounds of formula I for use as a second or further active substance, which has synergistic effect with other active substances in known medicaments, or administration of compounds of formula I together with such medicaments.
  • the present invention provides use of compounds of formula I as a prodrug or in other suitable form, which releases the active compound in vivo.
  • Target 4-substituted nucleosides were prepared by palladium-catalyzed reactions or nucleophilic substitutions.
  • 2-Furyl group was introduced into position 4 by Stille coupling with 2-furyltributylstannane, 3-furyl and 2-benzofuryl groups by Suzuki reaction with corresponding boronic acids, methyl derivative was synthesised by palladium-catalyzed alkylation with trimethylalluminium and dimethylaminoderivative by nucleophilic substitution with dimethylamine. All these reactions led to benzoylated derivatives, which gave target free nucleosides by deprotection using sodium methoxide in methanol. Methoxy, amino and methylsulfanyl groups were introduced by nucleophilic substitution, benzoyl groups were deprotected under reaction conditions.
  • NMR spectra were recorded on a 400 MHz ( 1 H at 400 MHz, 13 C at 100.6 MHz), a 500 MHz ( 1 H at 500 MHz, 13 C at 125.7 MHz), or a 600 MHz ( 1 H at 600 MHz, 13 C at 150.9 MHz) spectrometer. Melting points were determined on a Kofler block and are uncorrected. Germicid UV bulb, model EUV-13B was used for photocyclization reactions. Optical rotations were measured at 25° C., and [ ⁇ ] D 20 values are given in 10 ⁇ 1 deg cm 2 g ⁇ 1 . High resolution mass spectra were measured using electrospray ionization.
  • 4,6-Dichloropyrimidine (2) was zincated according to modified literature procedure (Mosrin, M.; Knochel, Chem. Eur. J. 2009, 15, 1468-1477). 4,6-Dichloropyrimidine (2) (950 mg, 6.30 mmol) was dissolved in THF (10 ml) and added dropwise into an ice-cooled solution of (TMP) 2 Zn.MgCl 2 .LiCl in THF (0.35 M, 9.0 ml, 3.15 mmol) and the reaction mixture was stirred at 0° C. for 1 hour, then let to warm to r.t.
  • IR (ATR): v 3047, 2931, 2861, 2804, 2663, 1607, 1568, 1499, 1470, 1425, 1313, 1267, 1229, 1107, 1071, 917, 835, 783, 635.
  • Tricyclic base 5 (150 mg; 0.7 mmol) was dissolved in MeCN (30 ml) and BSA (175 ⁇ l, 0.7 mmol) was added. The reaction mixture was heated at 60° C. for 30 minutes, then, TMSOTf (316 ⁇ l, 1.75 mmol) and 1-O-acetyl-2,3,5-tri-O-benzoyl- ⁇ -D-ribofuranose (724 mg, 1.4 mmol) were added. The mixture was heated to 60° C. for 12 hours. After cooling to r.t., the mixture was extracted with EtOAc and water, organic layer was washed with NaHCO 3 and again with water, dried over MgSO 4 and evaporated under reduced pressure.
  • nucleoside 6 250 mg, 0.38 mmol
  • furan-3-boronic acid 85 mg, 0.76 mmol
  • K 2 CO 3 157 mg, 0.76 mmol
  • Pd(PPh 3 ) 4 22 mg, 0.019 mmol
  • Solvent was evaporated and the crude product was purified by column chromatography (hexane/EtOAc, 0 ⁇ 20%).
  • Nucleoside 7b containing 30% of impurities (312 mg, 83%) was obtained as a yellow solid and was directly deprotected.
  • MTT test was used for in vitro evaluation of antitumor activities of newly synthesized compounds on cell lines derived from normal tissues or tumors.
  • cell lines K562 human acute myeloid leukemia
  • K562-Tax human acute myeloid leukemia, paclitaxel resistant subline, overexpress multiple drug resistant protein PgP
  • CEM T-lymfoblastic leukemia
  • CEM-DNR-bulk T-lymfoblastic leukemia, doxorubicin resistant
  • A549 human lung adenocarcinoma
  • HCT116 wt human colorectal cancer, wild-type
  • HCT116p53 ⁇ / ⁇ (human colorectal cancer, mutant p53) a U2OS human bone osteosarcoma
  • the tested compounds showed activity in in vitro cytotoxic test (Table 4), and it was selective against broad spectrum of cancer cell lines of various histogenetic origin (mesenchymal or epitelial tumors) with significantly lower activity against normal human fibroblasts (BJ and MRC-5 cell lines were tested). Active compounds showed promising therapeutic indexes (15-2500). IC 50 values of compounds 1c, if were in micromolar range, IC 50 values of compounds 1d, 1g, 1h were sub-micromolar to nanomolar. Cytotoxic activity against cancer cells was independent on p53 gene status, same activities were found for HCT116 (p53 wild type) and for mutant line with deleted gene HCT116 (p53 ⁇ / ⁇ ). However, a number of derivatives showed lower cytotoxicity against cells overexpressing transport proteins (mdr-1 for K562-TAX line and mrp-1 for CEM-DNR).
  • the compounds of this invention can be used as medicaments or components of medicaments for treatment of cancer and leukemia.

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  • Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
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  • Engineering & Computer Science (AREA)
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  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Saccharide Compounds (AREA)
US16/098,068 2016-06-29 2016-06-29 Substituted thienopyrrolopyrimidine ribonucleosides for therapeutic use Expired - Fee Related US10414788B2 (en)

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CZ308104B6 (cs) 2018-03-12 2020-01-08 Ăšstav organickĂ© chemie a biochemie AV ÄŚR, v. v. i. Pyridinopyrrolopyrimidinové ribonukleosidy pro terapeutické použití

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2009089804A1 (en) 2008-01-18 2009-07-23 Institute Of Organic Chemistry And Biochemistry As Cr, V.V.I. Novel cytostatic 7-deazapurine nucleosides
WO2010121576A2 (en) 2009-04-22 2010-10-28 Institute Of Organic Chemistry And Biochemistry Ascr,V.V.I. Novel 7-deazapurine nucleosides for therapeutic uses

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009089804A1 (en) 2008-01-18 2009-07-23 Institute Of Organic Chemistry And Biochemistry As Cr, V.V.I. Novel cytostatic 7-deazapurine nucleosides
WO2010121576A2 (en) 2009-04-22 2010-10-28 Institute Of Organic Chemistry And Biochemistry Ascr,V.V.I. Novel 7-deazapurine nucleosides for therapeutic uses

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chung et al., Journal of Medicinal Chemistry, American Chemical Society, US, vol. 23 (11), Nov. 1980, pp. 1158-1166 (Year: 1980). *
Chung, Fung-Lung, et al., "Synthesis of Certain [6:5:6] Linear Tricyclic Nucleosides as Potential Antitumor Agents", Journal of Medicinal Chemistry, American Chemical Society, US, vol. 23, No. 11, Nov. 1, 1980, pp. 1158-1166.
International Search Report and Written Opinion for corresponding PCT application No. PCT/CZ2016/050021, dated Oct. 7, 2016.

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CA3029170A1 (en) 2018-01-04
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US20190144487A1 (en) 2019-05-16
JP6650074B2 (ja) 2020-02-19
EP3478701A1 (en) 2019-05-08
EP3478701B1 (en) 2022-08-10
CA3029170C (en) 2021-02-16

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